Abstract Description CD4+ Foxp3+ regulatory T cells (Tregs) are critical for maintaining immune tolerance and tissue homeostasis. Recent studies suggest that Tregs undergo transcriptional and epigenetic reprogramming upon residency in peripheral non-lymphoid tissues (NLTs), yet whether they also adapt metabolically to support tissue-specific functions remains unclear. In secondary lymphoid organs (SLOs), Tregs rely on mitochondrial oxidative phosphorylation, but the metabolic requirements of NLT Tregs are less understood. To investigate this, we employed Single Cell ENergetIc metabolism by profiling Translation inHibition (SCENITH) assay, to assess the metabolic dependencies and capacities of NLT Tregs. Our results show that, in contrast to SLO Tregs, NLT Tregs exhibit high glycolytic capacity and dependency. Genetic ablation of key glycolytic regulators impaired Treg accumulation in certain NLTs. These findings highlight a distinct metabolic profile of NLT Tregs, suggesting that glycolysis plays an important role in their tissue-specific adaptation. This metabolic adaptation may offer novel therapeutic targets to modulate NLT Treg function in autoimmune and inflammatory diseases. Funding Sources NIH/NIDDK 1R01DK128061 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
Diaz-Saldana et al. (Sat,) studied this question.
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